Dosage Form Comprising Therapeutic Formulation

ABSTRACT

A dosage form is disclosed comprising a semipermeable walled container that houses a capsule, which capsule comprises a drug formulation, a piston, and an osmotic composition. The dosage form delivers the drug formulation through a passageway at a controlled rate over a sustained-release period of time up to 24 hours.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.10/373529, filed Feb. 24, 2003, which is a continuation of U.S.application Ser. No. 09/353519, filed Jul. 14, 1999, now U.S. Pat. No.6,551,613, which claims the benefit of U.S. Provisional Application No.60/099401, filed Sep. 8,1998, the disclosures of all of which are herebyincorporated by reference.

FIELD OF THE INVENTION

The present invention pertains to both a useful dosage form and to theprocess of manufacturing the dosage form. More particularly, theinvention relates to a dosage form comprising a wall that surrounds aninternal compartment comprising a therapeutic formulation, a piston, adriving member, and a passageway for delivering the therapeuticformulation from the dosage form. The invention concerns also a processfor manufacturing the dosage form comprising the steps of uniting thecomponents of the dosage form into the manufactured dosage form. Theinvention relates also to a method of using the dosage form fordispensing the therapeutic formulation at a controlled rate over asustained-release period of time.

BACKGROUND OF THE INVENTION

In the fields of pharmacy and medicine, many drugs are blended with apharmaceutically acceptable carrier for administering to a patient. Forexample, many drugs are administered to a patient by dissolving the drugin an aqueous or in a non-aqueous pharmaceutically acceptable carrier,by suspending the drug in a pharmaceutically acceptable solvent, or byincorporating the drug into one of two phases of an acceptable oil andwater system.

These pharmaceutical preparations are useful as they can be formulatedfor different routes of administration, including oral use,administering into body openings such as the vagina and anus, or appliedtopically. Their dose can be adjusted, and they can be administered tochildren and adults.

The preparation of these pharmaceutical preparations involvesconsiderations on the part of the pharmacist, including the purpose ofthe drug, internal or external use, concentration of the drug, thepharmaceutical carrier, and other characteristics that lead to the finalpharmaceutical preparation. However, there are serious shortcomingsassociated with these pharmaceutical preparations; mainly, the absenceof a dosage form for administering the pharmaceutical preparations at acontrolled rate over a sustained-release period for administering thedrug for a therapeutic benefit.

It will be appreciated by those versed in the drug dispensing art inview of the above presentation, that if a dosage form is made availablefor delivering pharmaceutical formulations that overcomes tribulationsof the prior art, such a dosage form would have a practical value in thedrug dispensing art. Likewise, it will be scientifically self-evident tothose versed in the drug delivery art, that if a dosage form is madeavailable that can administer pharmaceutical formulations comprising theprescribed dose at a sustained-release and controlled rate, such anunexpected dosage form would have an immediate acceptance for positivetherapy in both human and veterinary medicine.

OBJECTS OF THE INVENTION

Accordingly, in view of the above presentation it is an immediate objectof the invention to provide a dosage form that can deliver apharmaceutical formulation and thereby overcome the tribulations of theprior art.

Yet another object of the invention is to provide a dosage form that candeliver a pharmaceutical formulation at a sustained-release andcontrolled rate over an extended time.

Yet another object of this invention is to provide a dosage form thatcan deliver an initially dry pharmaceutical formulations that convertsto a liquid pharmaceutical formulation in the dosage form during the useof the dosage form in a liquid environment of use.

Another object of the invention is to provide a dosage form comprisingan internal capsule which comprises a liquid formulation containing adrug and a separate layer possessing expansion properties.

Another object of the invention is to provide a dosage form comprising anon-aqueous liquid formulation comprising an orally administrable drugthat can deliver a prescribed dose of drug to a patient in need oftherapy.

Another object of the invention is to provide a dosage form comprising aliquid formulation containing a liquid soluble drug that can bedispensed in a known dose for a therapeutic benefit.

Another object of the invention is to provide a dosage form comprising acapsule containing a non-aqueous liquid in which a protein orproteinaceous drug is dissolved or dispersed for sustained-releaseadministration at a controlled rate over time.

Another object of the invention is to provide a dosage form comprising acapsule that contains an emulsion-drug composition that can be deliveredat a controlled rate over a delivery period up to 30 hours.

Another object of the invention is to provide a dosage form comprising acapsule that comprises an expandable layer, a piston, and a liquidformulation.

Another object of the invention is to provide a dosage form comprising asemipermeable composition coated capsule that comprises a drug-emulsioncomposition.

Another object of the invention is to provide a process formanufacturing a dosage form, which process comprises the steps of addingto a capsule a composition containing a drug, placing a layer thatexpands when contacted by an aqueous fluid, closing the capsule, andcoating the capsules with a semipermeable coat.

Another object of the invention is to provide a process formanufacturing a dosage form comprising a capsule, which capsulecomprises an expandable layer, a piston, and a formulation containing aliquid and a drug.

Other objects, features, aspects and advantages of this invention willbe more apparent to those having ordinary skill in the drug delivery artfrom the accompanying specification taken in conjunction with thedrawings and the claims.

BRIEF DESCRIPTION OF DRAWINGS

In the drawing figures, which are not drawn to scale, but are set forthto illustrate operative embodiments of the invention, the drawingfigures are as follows:

FIG. 1 is a closed, general view of a dosage form provided by theinvention.

FIG. 2 is an opened view of the dosage form of FIG. 1, wherein in FIG. 2the dosage form is seen holding and storing a two piece capsulecomprising a body section and a cap section for containing a liquid drugformulation.

FIG. 3 is an opened view of the dosage form by FIG. 1, wherein in FIG. 3the dosage form is seen containing a capsule made as a unit piece whichcapsule contains a liquid drug formulation.

FIG. 4 is an opened view of the dosage form of FIG. 1 comprising acapsule comprising a body section and a cap section comprising a drugformulation and an osmotic composition, with the capsule surrounded by asemipermeable wall with an exit passageway.

FIG. 5 depicts a flow diagram for manufacturing a dosage form of theinvention.

In the drawing figures and in the specification, like parts in relatedfigures are identified by like numbers. The terms appearing earlier inthe specification, and in the description of the drawing figures, aswell as embodiments thereof, are further described in the disclosure.

DETAILED DESCRIPTION OF INVENTION

Turning now to the drawings in detail, which drawings are examples ofdosage forms provided by the invention, and which examples are not to beconsidered as limiting, one example of a dosage form is seen in FIG. 1.In FIG. 1, a dosage form 10, is seen in closed view, comprising a body11, a wall 12 and passageway 13. Wall 12 surrounds and forms an internalspace, not seen in FIG. 1. Dosage form 10 has a lead end 9 withpassageway 13 and a bottom end 8.

In drawing FIG. 2, dosage form 10 is seen comprising body 11, wall 12that surrounds and forms space 14. Wall 12 comprises orifice 13 thatconnects space 14 with the exterior environment of dosage form 10.Internal space 14 holds and stores a capsule comprising a body section16 and a cap section 17. The body section 16 is a component receivingsection that is filled with a drug 19 or section 16 is filled acomposition comprising drug 19 and a pharmaceutically acceptablecarrier, 18. The pharmaceutical carrier 18 can be initially dry, orinitially wet. A composition 21 comprising an expandable hydrophilicpolymer is present in the open end of body 16 and closed by sliding cap17 over body section 16. In the manufacture wherein body 16 comprises adry drug 19 composition, a solution or a suspension is formed in thecapsule by fluid being imbibed from the environment into the capsule formixing with the drug in situ.

The capsule is composed of two sections fitted together by slipping ortelescoping the cap section over the body section. This provides aclosed capsule whose capsule wall surrounds and encapsulates a usefuldry drug or liquid drug formulation. The capsule composed of two sectiondefines a hard capsule. Hard capsules are made by dipping stainlesssteel mold into a bath that contains a solution of a capsule wallforming material to coat the mold with the capsule wall-formingmaterial. The closed and filled capsule is coated next with acomposition comprising a semipermeable polymer. The semipermeablecomposition can be applied to the capsule sections before, or appliedafter, the sections are joined with the final capsule. In anothermanufacture, the hard two-section capsule can be made with each sectionhaving, matched locking rings near their opened end that permits joiningand locking the rings together near the overlapping cap and body afterfilling the capsule. In this manufacture, a pair of matched lockingrings are formed into the cap and into the body sections, and theserings provide the locking means for securely holding together thecapsule. The capsule can be manually filled with the formulation, or thecapsule can be machine filled with the formulation. In the finalmanufacture, the hard capsule is capsulated with a semipermeable wall onthe capsule's exterior surface. The semipermeable wall is permeable tothe passage of fluid and substantially impermeable to the passage ofdrug.

Dosage form 10, in capsule body 16 comprises in one manufacture aninitially dry drug formulation, or an initially liquid formulation. Thedry formulation comprises drug 19 and a pharmaceutically acceptablecarrier 18. The dry drug formulation, when dosage form 10 is inoperation in a fluid environment, imbibes fluid into dosage form 10 andself-converts from a dry formulation to a liquid drug formulation. Thedrug formulation comprises 100 ng to 1500 mg of drugs, or 0.5 wt % to 65wt % of a drug. Examples of drugs include progestins and estrogens. Theprogestins are represented by a member selected from the groupconsisting of progesterone, norethindrone, levonorgestrel, norgestimate,northindrone and 17-hydroxyprogesterone. The estrogenic steroids arerepresented by a member selected from the group consisting of estrogen,estradiol, estradiol valerate, estradiol benzoate, ethinyl estradiol,estrone, estrone acetate, estriol, and estriol triacetate.Representative of drug comprise also diphenedol, meclizine, anisidonie,diphenadione, diphenadione, erythrityl tetranitrate, dizoxin, reserpine,acetazolamide, bendroflumethiazide, chlorpropamide, tolazamide,phenaglycodol, allopurinol, aspirin, aluminum aspirin, metholrexate,acetyl sulfisoxazole, enitabas, and erythromycin.

The dosage form of the invention also delivers pharmacologically activepeptides, proteins, proteins anabolic hormones, growth promotinghormones, endocrine system hormones, porcine growth promoting hormone,bovine growth promoting hormone, equine growth promoting hormones,bovine growth promoting hormone, human growth promoting hormone,hormones derived from the pituitary and hypothalamus glands, recombinantDNA, somatropin, gonadotropic releasing hormone, follicle stimulatinghormone, luteinizing hormone, LH-RH, insulin, colchicine, chorionicgonadotropin, oxytocin, vasopressing adrenocorticothrophic hormone,prolactin, cosyntropin, bypressin, thyroid stimulating hormone,secretin, pancroezymin, enkephalin, glucagon, and like drugs. The drugsare disclosed in U.S. Pat. No. 4,111,201 issued to Theeuwes, and in U.S.Pat. No. 4,951,494 issued to Wong, Theeuwes, and Eckenhoff.

The dry pharmaceutically acceptable carrier for homogeneously blendingwith drug 19 to provide a dry drug formulation 19 are represented by apoly(alkylene oxide) of 50,000 to 300,000 weight average molecularweight, an alkali carboyalkylcellulose of 7,500 to 25,000 weight averagemolecular weight, a copoly (ethylene oxide-propylene oxide) polymer of4,000 to 25,000 weight average molecular weight, a polysaccharidecomprising hydroxyl and carboxyl groups possessing a 250,000 to 400,000weight average molecular weight, a poly(carboxylated vinyl) polymer, acyclodextrine, solid polymerized ethylene glycols, a thixotropic gelthat flows as a liquid but sets on standing during storage, and a solidpoly(ethylene glycol) comprising a molecular weight of 500 to 10,000.The poly(alkylene oxide) polymers are available from the Union CarbideCorporation, Dansbury, Conn.; the poly(ethylene glycols) are disclosedin Patty's Industrial Hygiene and Toxicology, by Clayton et al., Vol.2C, pages 3844-3852, and 3901-3907, (1982) published byWiley-Interscience Co.; alkalicarboxyalkylcellulose are commerciallyavailable from Hercules Co., Lafayette, Calif.; and the carbovinylpolymer are available from B.F. Goodrich Co., Cleveland, Ohio.

The dosage form 10 can comprise 0.5 wt % to 60 wt % of apharmaceutically acceptable liquid carrier. The pharmaceuticallyacceptable liquid can comprise a single component or it can comprisemore than one component. The pharmaceutically acceptable carrier cancomprise a surfactant, that serves to reduce aggregation, reduceinterfacial tension between components, enhance the free flow ofcomponents, and lessen the incidence of component retention in thedosage form. The drug formulation of this invention, in one embodimentcomprises a surfactant that imparts emulsification to the drugformulation. The surfactant can be a member selected from the groupconsisting of polyoxyethylenated castor oil comprising 9 moles ofethylene oxide, polyoxyethylenated castor oil comprising 15 moles ofethylene oxide, polyoxyethylenated castor oil comprising 20 moles ofethylene oxide, polyoxyethylenated castor oil comprising 25 moles ofethylene oxide, polyoxyethylenated castor oil comprising 40 moles ofethylene oxide, polyoxyethylenated castor oil comprising 52 moles ofethylene oxide, polyoxyethylendated sorbitan monopalmitate comprising 20moles of ethylene oxide, polyoxyethylenated sorbitan monostearatecomprising 4 moles of ethylene oxide, polyoxyethylenated sorbitantristearate comprising 20 moles of ethylene oxide, polkyoxyethylenatedstearic and comprising 8 moles of ethylene oxide, polyoxyethylene laurylether, polyoxyethylenated stearic acid comprising 40 moles of ethyleneoxide, polyoxyethylenated stearic acid comprising 30 moles of ethyleneoxide, polyoxyethylenated stearyl alcohol comprising 2 moles of ethyleneoxide, and polyoxyethylenated oleyl alcohol comprising 2 moles ofsurfactant. The surfactants are available from Atlas ChemicalIndustries, Wilmington, Del.; Drew Chemical Corp., Boonton, N.J.; andGAF Corp., New York, N.Y.

The drug formulation can comprise an oil phase, blended with the drugand the surfactant. The oil phase comprises a pharmaceuticallyacceptable oil that is non-polar in nature, or non-polar aftersynthesis. The oil can be an edible liquid such as a non-polar ester ofan unsaturated fatty acid, or mixtures of such esters can be utilizedfor this purpose. The oil can be vegetable, mineral, animal, or marinein origin. Examples of non-toxic oils comprise a member selected fromthe group consisting of peanut oil, cottonseed oil, sesame oil, oliveoil, corn oil, almond oil, mineral oil, castor oil, coconut oil, palmoil, cocoa butter oil, safflower oil, a mixture of moni- anddi-gylcerides of 16 to 18 carbon atoms, unsaturated fatty acids,fractionated trigylcerides derived from coconut oil, and fractionatedliquid triglycerides derived from short chain 10 to 15 carbon atom fattyacid, acetylated monoglycerides, acetylated triglycerides, olein knownalso as glycerol trioleate, palmitin known also as glyceroltripalmitate, stearin known also as glycerol tristearate, lauric acidhexylester, olein acid oleylester, glycolyzed ethoxylated, glyceride ofnatural oils, branched fatty acids with 13 molecules of ethylene oxide,olein acid decylester, and branched liquid fatty acids.

The pharmaceutically acceptable liquid carrier also embraces liquidprepolymers, emulsions of the single phase and two-phase types such asoil-in-water and water-in-oil, emulsions of castor oil in aqueoussolution of pigskin gelatin, emulsion of gum arabic, oils withemulsifiers such as mono- or di-gylcerides of a fatty acid, and lecithinand a fatty acid ester. The concentration of oil, or oil derivatives inthe drug liquid formulation is 1 wt % to 50 wt %, with the wt % of allcomponents in the drug liquid formulation equal to 100 wt %. The oilsare disclosed in Pharmaceutical Sciences by Remington, 17th Ed., pg.403-405 (1985) published by Mack Publishing Co., in Encyclopedia ofChemistry, by Van Nostrand Reinhold Co., 4th Ed., pg. 644 to 645 (1984)published by Van Nostrand Co.; in U.S. Pat. No. 4,259,323 issued toRanucci; and in U.S. Pat. No. 3,905,360 issued to Zaffaroni.

Dosage form 10 in capsule body 16 comprises an expandable composition 21that expands in the presence of imbibed aqueous and biological fluids.Body 16 comprising expandable composition 21 is closed by cap 17, toprovide a closed capsule in dosage form 10. Composition 21 is anexpandable push driving force that acts in cooperation with dosage form10 for delivering drug 19 from dosage form 10. Composition 21 exhibitsfluid imbibing and/or absorbing properties. Composition 21 comprises ahydrophilic polymer that can interact with water and aqueous biologicalfluids and then swell or expand. The hydrophilic polymers are known alsoas osmopolymers, osmogels and hydrogels, and they exhibit aconcentration gradient across wall 12, whereby they imbibe fluid intodosage form 10. Representative of hydrophilic polymers are poly(alkyleneoxide) of 1,000,000 to 10,000,000 weight-average molecular weightincluding poly(ethylene oxide), and an alkali carboxymethylcellulose of10,000 to 6,000,000 weight average molecular weight including sodiumcarboxymethylcellulose. Composition 21 comprises 10 mg to 425 mg ofosmopolymer. Composition 21 can comprise 1 mg to 50 mg of apoly(cellulose) of a member selected from the group consisting ofhydroxyethylcellulose, hydroxyproylcellulose,hydroxypropylmethylcellulose, and hydroxypropylbutylcellulose.Composition 21 comprises 0.5 mg to 175 mg of an osmotically effectivesolute, known also as osmotic solute and osmagent, that imbibe fluidthrough wall 12 into dosage form 10. The osmotically effective solutesare selected from the group consisting of a salt, acid, amine, ester andcarbohydrate. Representative osmagents are selected from the groupconsisting of magnesium sulfate, magnesium chloride, potassium sulfate,sodium sulfate, lithuim sulfate, potassium acid phosphate, mannitol,urea, inositol, magnesium succinate, tartaric acid, sodium chloride,potassium chloride, and carbohydrates such as raffinose, sucrose,glucose, lactose, and sorbitol. Composition 21 optionally comprises 0 wt% to 3.5 wt % of a colorant, such as ferric oxide. The total weight ofall components in composition 21 is equal to 100 wt %.

Dosage form 10 comprises a wall 12 that surrounds the internal capsule.Wall 12 comprises a composition permeable to the passage of fluid,aqueous and biological fluid, present in environment of use, in animalincluding a human, and wall 12 is substantially impermeable to thepassage of drug 19, and the components of emulsion formulation 19. Wall12 is nontoxic, and it maintains its physical and chemical integrityduring the drug delivery device of dosage form 10. Representative ofmaterials for forming wall 12, include semipermeable polymers,semipermeable homopolymers, semipermeable copolymer, and semipermeableterpolymers. The polymers comprise polymers including cellulose esters,cellulose ethers, and cellulose ester-esters. These cellulosic polymershave a degree of substitution, D.S., on their anhydroglucose unit fromgreater than 0 up to 3 inclusive. By degree of substitution is meant theaverage number of hydroxyl groups originally present on theanhydroglucose unit that are replaced by a substituting group, orconverted into another group. The anhydroglucose unit can be partiallyor completely substitute with groups such as acyl, alkanoyl, alkenoyl,aroyl, alkyl, alkoxy, halogen, carboalkyl, alkylcarbamate,alkylcarbonate, alkylsulfonate, alkylsulfamate, and semipermeablepolymer forming groups.

The semipermeable materials typically include a member selected from thegroup consisting of cellulose acylate, cellulose diacylate, cellulosetriacetate, cellulose acetate, cellulose diacetate, cellulosetriacetate, mono-, di- and tri-cellulose alkanylates, mono-, di-, andtri-alkenylates, mono-, di-, and tri-aroylates, and the like. Examplarypolymers including cellulose acetate having a D.S. of 1.8 to 2.3 and anacetyl content of 32 to 39.9%; cellulose diacetate having a D.S. of 1 to2 and an acetyl content of 21 to 35%; cellulose triacetate having a D.S.of 2 to 3 and an acetyl content of 34 to 44.8%; and the like. Morespecific cellulosic polymers include cellulose proprionate having a D.S.of 1.8 and a propionyl content of 38.5%; cellulose acetate propionatehaving an acetyl content of 1.5 to 7% and an acetyl content of 39 to42%; cellulose acetate propionate having an acetyl content of 2.5 to 3%,an average propionyl content of 39.2 to 45% and a hydroxyl content of2.8 to 5.4%; cellulose acetate butyrate having a D.S. of 1.8, an acetylcontent of 13 to 15%, and a butyryl content of 34 to 39%; celluloseacette butyrate having an acetyl content of 2 to 29.5%, a butyrylcontent of 17 to 53%, and a hydroxyl content of 0.5 to 4.7%; cellulosetriacylates having a D.S. of 2.9 to 3 such as cellulose trivalerate,cellulose trilaurate, cellulose tripalmitate, cellulose trioctanoate,and cellulose tripropionate; cellulose diesters having a D.S. of 2.2 to2.6 such as cellulose disuccinate, cellulose dipalmitate, cellulosedioctanoate, cellulose dicarpylate and the like; mixed cellulose esterssuch as cellulose acetate valerate, celluloser acetate succinate,cellulose propionate succinate, cellulose acetate octanoate, cellulosevalerate palmitate, cellulose acetate heptonate, cellulose valeratepalmitate, cellulose acetate heptonate, and the like. Semipermeablepolymers are known in U.S. Pat. No. 4,077,407, and they can be made byprocedures described in Encyclopedia of Polymer Science and Technology,Vol. 3, pages 325 to 354, 1965, published by Interscience Publishers,Inc., New York.

Additional semipermeable polymers include cellulose acetaldehydedimethyl acetate; cellulose acetate ethylcarbonate; cellulose acetatemethylcarbamate; cellulose dimethylaminoacetate; semipermeablepolyamides; semipermeable polyurethanes; semipermeable sulfonatedpolystyrenes; cross-linked, selectively semipermeable polymers formed bythe coprecipitation of a polyanion and a polycation as disclosed in U.S.Pat. Nos. 3,173,876; 3,276,586; 3,541,005; 3,541,006; and 3,546,142;semipermeable polymers as disclosed by Loeb and Sourirajan in U.S. Pat.No. 3,133,132; semipermeable polystyrene derivatives; semipermeablepoly(sodium styrenesulfonate); semipermeablepoly(vinylbenzyltrimethyl)ammonium chloride; semipermeable polymersexhibiting a fluid permeability of 10 to 10 (cc.mil/cm.hr.atm) expressedas per atmosphere of hydrostatic or osmotic pressure difference across asemipermeable wall. The polymers are known to the art in U.S. Pat. Nos.3,845,770; 3,916,899; and 4,160,020, and in Handbook of Common Polymers,by Scott, J. R. and Ross, W. J., 1971, published by CRC Press,Cleveland, Ohio.

Drawing FIG. 3 illustrates another dosage form 10 provided by thisinvention. In FIG. 3, dosage form 10 comprises a body 11, comprisingwall 12 with a passageway 13. Wall 12 surrounds and defines internalcompartment 14 housing internal capsule 20. Internal capsule 20 in itsfinal manufacture comprises a one piece capsule that distinguishescapsule 20 from the two piece capsule presented above. Capsule 20comprises a composition comprising drug 19 and pharmaceuticallyacceptable carrier 18 as presented above. Capsule 20 comprises alsocomposition 21, the expandable composition presented above. Capsule 20in drawing FIG. 3 comprises a movable piston 22. The movable piston 22moves or slides in response to pressure generated inside capsule 20. Thepiston 22 is positioned between and in contacting relation with theliquid formulation and expandable composition 21. The piston 22 servesto reduce diffusion and/or migration between the liquid drug formulationand the expandable composition, thereby maintaining the concentration ofthe liquid formulation, and the piston 22 also prevents interactionbetween the liquid formulation and the expandable composition, therebymaintaining the stability of the liquid formulation.

Dosage form 10 in operation imbibes fluid through wall 12 causingcomposition 19 to expand and apply pressure against piston 22. Thisapplied pressure moves piston 22 towards passageway 13, whereby theliquid drug formulation is pushed through passageway into theenvironment of use. Representative of materials for manufacturingmovable piston 22 comprise a member selected from the group consistingof a wax, petroleum wax, an ester of a high molecular weight fatty acidwith a high molecular weight alcohol, a piston formed of an olefinpolymer, a condensation polymer, rubber, organosilicon, high densitypolyethylene, high density polypropylene, and piston forming materialsimpermeable to fluid.

In FIG. 3, capsule 20 is surrounded and/or coated by semipermeable wall12 presented above. Capsule 20 in FIG. 3 comprises a sealed constructionencapsulating the drug formulation, the piston, and the expandablecomposition. The capsule is made by various processes including theplate process, the rotary die process, the reciprocating die process,and the continuous process. The place process uses a set of molds. Awarm sheet of a prepared capsule lamina-forming material is laid overthe lower mold and the formulation poured on it. A second sheet of thelamina-forming material is placed over the formulation followed by thetop mold. The mold set is placed under a press and a pressure applied,with or without heat to form a unit, capsule. The capsules are washedwith a solvent for removing excess agent formulation from the exteriorof the capsule, and the air-dried capsule is encapsulated with asemipermeable wall.

The rotary die process uses two continuous films of capsulelamina-forming material that are brought into convergence between a pairof revolving dies and an injector wedge. The process fills and seals thecapsule in dual and coincident operations. In this process, the sheetsof capsule lamina-forming material are fed over guide rolls, and thendown between the wedge injector and the die rolls. The agent formulationto be capsuled flows by gravity into a positive displacement pump. Thepump meters the agent formulation through the wedge injector and intothe sheets between the die rolls. The bottom of the wedge contains smallorifices lined up with the die pockets of the die rolls. The capsule isabout half-sealed when the pressure of pumped agent formulation forcesthe sheets into the die pockets, wherein the capsules are simultaneouslyfilled, shaped, hermetically sealed and cut from the sheets oflamina-forming materials. The sealing of the capsule is achieved bymechanical pressure on the die rolls and by heating of the sheets oflamina-forming materials by the wedge. After manufacture, the agentformulation-filled capsules are dried in the presence of forced air, anda semipermeable lamina capsuled thereto, by processes describedhereafter.

The reciprocating die process produces capsules by leading two films ofcapsule lamina-forming material between a set of vertical dies. The diesas they close, open, and close perform as a continuous vertical plateforming row after row of pockets across the film. The pockets are filledwith agent formulation, and as the pockets move through the dies, theyare sealed, shaped and cut from the moving film as capsules filled withagent formulation. A semipermeable capsulating lamina is coated thereonto yield the capsule. The continuous process is a manufacturing systemthat also uses rotary dies with the added feature that the process cansuccessfully fill active agent in dry power form into a soft capsule, inaddition to encapsulating liquids. The filled, capsule of the continuousprocess is encapsulated with a semipermeable polymeric material to yieldthe capsule. Procedures for manufacturing unit capsules are disclosed inU.S. Pat. No. 4,627,850 issued to inventors Deters, Theeuwes, Mullins,and Eckenhoff.

Drawing FIG. 4 illustrates another dosage form 10 provided by theinvention. In drawing FIG. 4, dosage form 10 comprises lead end 9,trailing end 8, capsule cap 17, drug 19 and carrier 18 in capsule body16, expandable composition 21 in capsule body 16 closed by capsule cap17. The components comprising FIG. 4 were presented above, and thatpresentation is incorporated herein.

In drawing FIG. 4, dosage form 10 comprises wall 12 made from aninjection-moldable composition by an injection-molding techniques.Injection-moldable compositions provided for injection-molding into wall12 comprise a thermoplastic polymer, or the compositions comprise amixture of thermoplastic polymers and optional injection-moldingingredients. The thermoplastic polymer that can be used for the presentpurpose comprise polymers that have a low softening point, for example,below 200° C., preferably within the range of 40° C. to 180° C. Thepolymers, are preferably synthetic resins, for example, linearpolycondensation resins, condensation polymerized resins, additionpolymerized resins, such as polyamides, resins obtained from diepoxidesand primary alkanolamines, resins of glycerine and phthalic anhydrides,polymethane, polyvinyl resins, polymer resins with end-positions free oresterified carboxyl or carboxamide groups, for example with acrylicacid, acrylic amide, or acrylic acid esters,, polycaprolactone, and itscopolymers with dilactide, diglycolide, valerolactone and decalactone, aresin composition comprising polycaprolactone and polyalkylene oxide,and a resin composition comprising polycaprolactone, a polyalkyleneoxide such as polyethylene oxide, poly(cellulose) such aspoly((hydroxypropylmethylcellulose), poly(hydroxyethylmethylcellulose),poly(hydroxyethylcellulose), and poly(hydroxypropylkcellulose). Themembrane forming composition can comprises optical membrane-formingingredients such as polyethylene glycol, talcum, polyvinylalcohol,lactose, or polyvinyl pyrrolidone. The compositions for forming aninjection-molding polymer composition can comprise 100% thermoplasticpolymer. The composition in another embodiment comprises 10% to 99% of athermoplastic polymer and 1% to 70% of a different polymer with thetotal equal to 100%. The invention provides also a thermoplastic polymercomposition comprising 1% to 98% of a first thermoplastic polymer, 1% to90% of a different, second polymer and 1% to 90% of a different, thirdpolymer with all polymers equal to 100%. Representation compositioncomprises 20% to 90% of thermoplastic polycaprolactone and 10% to 80% ofpoly(alkylene oxide); a composition comprising 20% to 90% ofpoly(alkylene oxide); a composition comprising 20% to 90%polycaprolactone and 10% to 60% of poly(ethylene oxide) with theingredients equal to 100%; a composition comprising of 10% to 97%polycaprolactone, 10% to 97% poly(alkylene oxide), and 1% to 97% ofpoly(ethylene glycol) with all ingredients equal to 100%; a compositioncomprising 20% to 90% polycaprolactone and 10% to 80% of polyethyleneglycol 40 stearate (Myrj 525) with all ingredients equal to 100%; and acomposition comprising 1% to 90% polycaprolactone, 1% to 90%poly(ethylene oxide), 1% to 90% poly(hydroxypropylcellulose) and 1% to90% poly(ethylene glycol) with all ingredients equal to 100%. Thepercent, expressed is weight percent, wt %.

In another embodiment of the invention, a composition forinjection-molding to provide a membrane is prepared by blending acomposition comprising a polycaprolactone 63 wt %, polyethylene oxide 27wt %, and polyethylene glycol 10 wt % in a conventional mixing machine,such as a Moriyama ® Mixer at 65° C. to 95° C., with the ingredientsadded to the mixer in the following addition sequence, polycaprolactone,polyethylene oxide and polyethylene glycol. All the ingredients weremixed for 135 minutes at a rotor speed of 10 to 20 rpm. Next, the blendis fed to a Baker Perkins Kneader® extruder at a 80° C. to 90° C., at apump speed of 10 rpm and a screw speed of 22 rpm, and then cooled to 10°C. to 12° C. to reach a uniform temperature. Then, the cooled extrudedcomposition is fed to an Albe Pelletizer, converted into pellets at 250°C. and a length of 5 mm. The pellets next are fed into aninjection-molding machine, an Arburg Allrounder® at 200° F. to 350° F.(93° C. 177° C.), heated to a molten polymeric composition, and theliquid polymer composition forced into a mold cavity at high pressureand speed until the molded is filled and the composition comprising thepolymers are solidified into a preselected shape. The parameters for theinjection-molding consists of a band temperature through zone 1 to zone5 of the barrel of 195° F. (91° C.) to 375° F. (191° C.), aninjection-molding pressure of 1818 bar, a speed of 55 cm³/s, and a moldtemperature of 75° C. The injection-molding compositions andinjection-molding procedures are disclosed in U.S. Pat. No. 5,614,578issued to Dong, Wong, Pollock, and Ferrari.

The expression passageway as used herein denotes means and methodssuitable for releasing the useful, active drug emulsion formulation fromthe dosage form. The expression includes passage way, aperture, hole,bore, pore and the like through the semipermeable walls. The orifice canbe formed by mechanical drilling, laser drilling, or by eroding anerodible element, such as a gelatin plug, a pressed glucose plug, toyield the orifice, when the dosage form is in the environment of use. Inan embodiment, the orifice in wall 12 is formed in the environment ofuse in response to the hydrostatic pressure generated in dosage form 10.In another embodiment, the dosage form 10 can be manufactured with twoor more orifices in spaced-class relation for delivering drug 20 fromdosage form 10. The orifice 13, can be formed by mechanical rupturing ofwall 12 during operation of dosage form 10. A detailed description oforifices and the maximum and minimum dimensions of an orifice aredisclosed in U.S. Pat. Nos. 3,845,770 and 3,916,899 both issued toinventors Theeuwes and Higuchi.

EXAMPLES OF THE INVENTION

The following examples are illustrative of the present invention, andthe examples should not be considered as limiting the scope of thisinvention in any way, as these examples and other equivalents thereofwill become apparent to those versed in the drug dispensing art in thelight of the present disclosure, and the accompanying claims.

Example 1

A dosage form is manufactured for dispensing a beneficial drug orally tothe gastrointestinal tract as follows: first, a composition comprisingexpandable properties is prepared by adding 58.7 wt % sodiumcarboxymethylcellulose is added to the bowl of a fluid bed granulator.Next, 30 wt % of sodium chloride, 5.0 wt % hydroxyproplymethylcelluloseof 11,300 molecular weight and 1 wt % red ferric oxide are added to thefluid bed granulator. In a separate container, a granulating solution isprepared by dissolving 5.0 wt % hydroxypropylcellulose of 40,000molecular weight in purified water. Then, the granulating solution issprayed onto the fluidized powders until all the solution is applied andthe powders are granular. Next, 0.25 wt % of magnesium stearate isblended with the granular. The composition is compressed into a tabletwith a conventional tablet press, as follows: two hundred and fifty mgof the composition are added to a 9/32 inch punch, tamped and thencompressed under a force of about 1 metric ton into a expandable osmogeltablet.

Next, a drug formulation is prepared as follows: 50 wt % ofprogesterone, 33.4 wt % of polyoxyl 35 castor oil available as CremophorEl from BASF Corp., Mount Olive, N.J., and 16.5 wt % of acetylatedmonoglyceride available as Myvacet available from Eastman Corp.,Kingsport, Tenn., are mixed homogeneously using a standard homogenizer.

Then, a capsule comprising a gelatin wall, size 0, is separated into twosegments, its body and its cap. Then, 600 mg of the drug formulation isfilled into the body of the capsule followed by an osmotic tabletinserted into an injection-molded wall with the osmotic tablet facingthe bottom of the injection-molded walled housing. Finally, the wallsare crimped at about 68° C. to provide an exit passageway of 155 mil(3.875 mm).

Example 2

The procedure of Example 1 is repeated in the example for providing thedosage form except a piston is place in contact with the drugformulation followed by the expandable osmogel tablet prior to formingthe exit passageway in the injection-molded wall.

Example 3

The procedure of Example 1 is repeated in this example for providing thedosage form except in this example a piston is placed in contact withthe drug formulation, followed by the expandable osmogel tablet, withthe body of the capsule capped by the cap of the capsule prior toforming the exit passageway in the outer injection-molded wall.

Example 4

The procedure of Example 1 is followed for providing the dosage form,except in this example the drug formulation comprises 50 wt %progesterone, 37.5 wt % polyoxyl 35 castor oil, and 12.5 wt % acetylatedmonoglyceride.

Example 5

The procedure of Example 1 is repeated in this example for providing adosage form wherein the drug formulation comprises 50 wt % progesterone,25 wt % polyoxyl 35 castor oil and 25 wt % acetylated monoglyceride.

Example 6

The procedure of Example 1 is repeated in this example, except hereinthe drug formulation comprises 50 wt % progesterone and 50 wt % polyoxyl35 castor oil.

Example 7

The procedure of Example 2 is followed in this example for providing thedosage form, except in this example the drug formulation comprises thedrug formulation and the expandable osmogel tablet, the capsule body isclosed with the capsule cap, prior to being placed in theinjection-molded wall provided with an exit passageway.

Example 8

A dosage form is manufactured for dispensing a beneficial drug to thegastrointestinal tract of a human as follows: first, an expandablecomposition is prepared in a fluid bed granulator. The expandablecomposition comprises 30 wt % sodium chloride screened through a 20 meshscreen added to the granulator bowl, followed by 58.75 wt % polyethyleneoxide of 2,000,000 molecular weight. Then, 5 wt %hydroxypropylmethylcellulose possessing a 9,200 molecular weight and 1 %red ferric oxide is added to the granulator bowl. In a separate mixer, agranulation solution is prepared by dissolving 5 wt %hydroxypropylcellulose in purified water. Then, the granulating solutionis sprayed onto the fludized powders in the granulator until all thesolution is applied and the powders are granular. Next 0.25 wt %magnesium stearate is blended with the just prepared granules. Thegranules are compressed into a tablet-shaped layer comprising 250 mg ofgranules in a 9/32 inch punch, tamped, and then compressed under a forceof 1 metric ton to provide the osmogel driving tablet.

Next, a drug formulation is prepared as follows: first 50 wt % ofmicrofluidized acyclovir, 12.5 wt % polyoxyethylene 20 stearate, 25 wt %polyoxyl 35 castor oil available as Cremophor El® from BASF Corp., MountOlive, N.J., and 12.5 wt % polyoxyl 40 stearate commercially availableas Myrj® 52 from ICI Inc., Wilmington, Del. are blended in a homogenizerto provide a homogenous blend.

Next, a capsule made of pharmaceutically gelatin is separated into itsbody and cap. The body is first charged with the drug formulation,followed by a piston formed of high density polyethylene, which isfollowed by the expandable composition. The filled capsule body isclosed with the gelatin cap.

Next, the assembled capsule is coated with a semipermeable wall, whichis applied from a wall forming composition. Then wall-formingcomposition comprises 85 wt % cellulose acetate comprising a 39.8%acetyl content, and 15 wt % polyethylene glycol 3350. The wall formingcomposition is dissolved in acetone/methanol (80/20 wt/wt) cosolvent tomake 4% solid solution. The solution is sprayed onto the capsule in anair suspension coater. The semipermeable wall coated capsules are driedin an oven at 50° C. and 50° relative humidity for 1 day to remove allsolvents. Then, a passageway is drilled in the semipermeable wall toprovide the drug dispensing dosage form. Accompanying FIG. 5 depicts aflow chart of a process for manufacturing the dosage form of theinvention.

METHOD OF USING THE DOSAGE FORM

The invention provides also a method of administering a drug to a humanpatient. The method comprises orally admitting into the gastrointestinaltract of a human the dosage form provide by the invention. The methodcomprises the steps of (1) admitting orally the dosage form into thegastrointestinal tract, which dosage form comprises: (a) a wall forimbibing an external fluid, aqueous-biological, through the wall intothe dosage form, which wall surrounds; (b) a capsule, the capsulecomprising; (c) a drug formulation, a piston and an osmotic drivingforce; and (d) an exit in the semipermeable wall; (2) permitting imbibedaqueous fluid to dissolve the gelatin capsule; (3) letting imbibed fluidmix with the drug composition to form a dispensable composition; (4)letting imbibed fluid be absorbed by the osmotic driving compositionthereby causing the composition swell, expand and push the drugcomposition through the passageway at a controlled rate over asustained-release period up to twenty-four hours.

Inasmuch as the foregoing specification comprised representativeembodiments of the invention, it is understood that changes,modifications and variations can be made herein, in accordance with theinventive principles disclosed, without departing from the scope of theinvention.

1. A dosage form for oral administration of a drug comprising: acapsule; a drug formulation disposed in the capsule, the drugformulation comprising a dosage of the drug and a pharmaceuticallyacceptable carrier, the pharmaceutically acceptable carrier comprising amember selected from the group consisting of a poly(alkylene oxide) of50,000 to 300,000 weight average molecular weight, an alkali ofcarboxyalkylcellulose of 7,500 to 25,000 weight average molecularweight, a copoly(ethylene oxide-propylene oxide) of 4,000 to 25,000weight average molecular weight, a poly(carboxylated vinyl) polymer, apolysaccharide comprising hydroxyl and carboxyl groups of 250,000 to400,000 weight average molecular weight, a cyclodextrine, a solidpolymerized ethylene glycol, a thixotropic gel, a solid poly(ethyleneglycol) of 500 to 10,000 weight average molecular weight; an expandablecomposition disposed in the capsule, the expandable compositioncomprising an osmopolymer, an osmagent, and a member selected from thegroup consisting of hydroxyethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose, and hydroxypropylbutylcellulose, whereinthe expandable composition increases in volume in the presence of anaqueous fluid; a wall surrounding the capsule, the wall comprising acomposition that is permeable to passage of fluid and substantiallyimpermeable to passage of the drug; an exit in the wall for releasingthe drug formulation from the capsule at a sustained release rate overan extended period of time; and a movable piston positioned between thedrug formulation and the expandable composition, the movable pistonbeing in contacting relation with the drug formulation and theexpandable composition.
 2. The dosage form of claim 1, wherein theexpandable composition comprises sodium carboxymethylcellulose, sodiumchloride, and hydroxypropylmethycellulose.
 3. The dosage form of claim2, wherein the drug formulation comprises progesterone, polyoxyl 35castor oil, and acetylated monoglyceride.
 4. The dosage form of claim 1,wherein the expandable composition comprises polyethylene oxide, sodiumchloride, and hydroxypropylmethylcellulose.
 5. The dosage form of claim4, wherein the polyethylene oxide possesses a molecular weight of2,000,000, and the hydroxypropylmethylcellulose possesses a molecularweight of 9,200.
 6. The dosage form of claim 4, wherein the drugformulation comprises acyclovir, polyoxyethylene 20 stearate, polyoxyl35 castor oil, and polyoxyl 40 stearate.
 7. The dosage form of claim 6,wherein the wall surrounding the capsule comprises cellulose acetate andpolyethylene glycol.
 8. The dosage form of claim 1, wherein the wallsurrounding the capsule is made of an injection-moldable compositioncomprising a thermoplastic polymer.
 9. The dosage form of claim 1,wherein the drug comprises a member selected from the group consistingof progestins and estrogens.
 10. The dosage form of claim 1, wherein thedrug formulation further comprises a surfactant selected from the groupconsisting of polyoxyethylenated castor oil comprising 9 moles to 52moles of ethylene oxide, polyoxyethylenated sorbitan monopalmitatecomprising 20 moles of ethylene oxide, polyoxyethylenated sorbitanmonostearate comprising 4 moles of ethylene oxide, polyoxyethylenatedsorbitan tristearate comprising 20 moles of ethylene oxide,polyoxyethylenated lauryl ether, polyoxyethylenated stearic acidcomprising 30 moles to 40 moles of ethylene oxide, polyoxyethylenatedstearyl alcohol comprising 2 moles of ethylene oxide, andpolyoxyethylenated oleyl alcohol comprising 2 moles of ethylene oxide.11. The dosage form of claim 1, wherein the drug comprises a memberselected from the group consisting of peptide, protein, protein anabolichormone, growth promoting hormone, endocrine system hormone, porcinegrowth promoting hormone, bovine growth promoting hormone, equine growthpromoting hormone, human growth hormone, hormones derived from thepituitary gland, hormones derived from the hypothalamus gland,recombinant DNA, somatropin, gonadotropic releasing hormone, folliclestimulating hormone, luteinizing hormone, LH-RH, insulin, cochicine,chorionic gonadotropin hormone, oxytocin, vasopressingadrenocorticothropic hormone, prolactin, cosyntropin, bypressin, thyroidstimulating hormone, secretin, pancroezymin, enkephalin, and glucagon.12. The dosage form of claim 1, wherein the extended period of time isup to twenty-four hours.
 13. A method for administering a drug to arecipient, comprising the steps of: administering to the recipient adosage form comprising: a capsule; a drug formulation disposed in thecapsule, the drug formulation comprising a dosage of the drug and apharmaceutically acceptable carrier, the dry pharmaceutically acceptablecarrier comprising a member selected from the group consisting of apoly(alkylene oxide) of 50,000 to 300,000 weight average molecularweight, an alkali of carboxyalkylcellulose of 7,500 to 25,000 weightaverage molecular weight, a copoly(ethylene oxide-propylene oxide) of4,000 to 25,000 weight average molecular weight, a poly(carboxylatedvinyl) polymer, a polysaccharide comprising hydroxyl and carboxyl groupsof 250,000 to 400,000 weight average molecular weight, a cyclodextrine,a solid polymerized ethylene glycol, a thixotropic gel, a solidpoly(ethylene glycol) of 500 to 10,000 weight average molecular weight;an expandable composition disposed in the capsule, the expandablecomposition comprising an osmopolymer, an osmagent, and a memberselected from the group consisting of hydroxyethylcellulose,hydroxypropylcellulose, hydroxypropylmethylcellulose, andhydroxypropylbutylcellulose, wherein the expandable compositionincreases in volume in the presence of an aqueous fluid; a wallsurrounding the capsule, the wall comprising a composition that ispermeable to passage of fluid and substantially impermeable to passageof the drug; an exit in the wall for releasing the drug formulation fromthe capsule at a sustained release rate over an extended period of time;and a movable piston positioned between the drug formulation and theexpandable composition, the movable piston being in contacting relationwith the drug formulation and the expandable composition;
 14. The methodof claim 13, wherein administering to the recipient a dosage formcomprises administering to the recipient the dosage form wherein theexpandable composition comprises sodium carboxymethylcellulose, sodiumchloride, and hydroxypropylmethycellulose.
 15. The method of claim 14,wherein administering to the recipient a dosage form comprisesadministering to the recipient the dosage form wherein the drugformulation comprising progesterone, polyoxyl 35 castor oil, andacetylated monoglyceride.
 16. The method of claim 13, whereinadministering to the recipient a dosage form comprises administering tothe recipient the dosage form wherein the expandable compositioncomprises polyethylene oxide, sodium chloride, andhydroxypropylmethylcellulose.
 17. The method of claim 16, whereinadministering to the recipient a dosage form comprises administering tothe recipient the dosage form wherein the drug formulation comprisesacyclovir, polyoxyethylene 20 stearate, polyoxyl 35 castor oil, andpolyoxyl 40 stearate.
 18. The method of claim 17, wherein administeringto the recipient a dosage form comprises administering to the recipientthe dosage form wherein the drug formulation comprises acyclovir,polyoxyethylene 20 stearate, polyoxyl 35 castor oil, and polyoxyl 40stearate.
 19. The method of claim 18, wherein administering to therecipient a dosage form comprises administering to the recipient thedosage form wherein the wall surrounding the capsule comprises celluloseacetate and polyethylene glycol.
 20. The method of claim 13, whereinadministering to the recipient a dosage form comprises administering tothe recipient the dosage form wherein the drug comprises a memberselected from the group consisting of progestins and estrogens.